Plasmodium berghei Circumvents Immune Responses Induced by Merozoite Surface Protein 1- and Apical Membrane Antigen 1-Based Vaccines

Abstract

BackgroundTwo current leading malaria blood-stage vaccine candidate antigens for Plasmodium falciparum, the C-terminal region of merozoite surface protein 1 (MSP119) and apical membrane antigen 1 (AMA1), have been prioritized because of outstanding protective efficacies achieved in a rodent malaria Plasmodium yoelii model. However, P. falciparum vaccines based on these antigens have had disappointing outcomes in clinical trials. Discrepancies in the vaccine efficacies observed between the P. yoelii model and human clinical trials still remain problematic.Methodology and ResultsIn this study, we assessed the protective efficacies of a series of MSP119- and AMA1-based vaccines using the P. berghei rodent malarial parasite and its transgenic models. Immunization of mice with a baculoviral-based vaccine (BBV) expressing P. falciparum MSP119 induced high titers of PfMSP119-specific antibodies that strongly reacted with P. falciparum blood-stage parasites. However, no protection was achieved following lethal challenge with transgenic P. berghei expressing PfMSP119 in place of native PbMSP119. Similarly, neither P. berghei MSP119- nor AMA1-BBV was effective against P. berghei. In contrast, immunization with P. yoelii MSP119- and AMA1-BBVs provided 100% and 40% protection, respectively, against P. yoelii lethal challenge. Mice that naturally acquired sterile immunity against P. berghei became cross-resistant to P. yoelii, but not vice versa.ConclusionThis is the first study to address blood-stage vaccine efficacies using both P. berghei and P. yoelii models at the same time. P. berghei completely circumvents immune responses induced by MSP119- and AMA1-based vaccines, suggesting that P. berghei possesses additional molecules and/or mechanisms that circumvent the host's immune responses to MSP119 and AMA1, which are lacking in P. yoelii. Although it is not known whether P. falciparum shares these escape mechanisms with P. berghei, P. berghei and its transgenic models may have potential as useful tools for identifying and evaluating new blood-stage vaccine candidate antigens for P. falciparum.

Kinetics of Humoral and Memory B Cell Response Induced by the Plasmodium falciparum 19-Kilodalton Merozoite Surface Protein 1 in Mice

“…Although immunization with PfMSP-1 19 induced memory antibody responses that reacted strongly with the native PfMSP-1 19 on the blood-stage parasite, antibodies were not effective at protecting mice against P. berghei transgenic parasite challenge infection. PfMSP-1 19 -specific memory B cells failed to reduce the parasite load significantly and did not prolong the survival time of the infected mice, consistent with findings reported earlier (51). A previous study had shown that the significant reduction in numbers of Plasmodium yoelii MSP-1 19 -specific ASCs was because MBCs either underwent early apoptosis or were not activated after antigen reexposure, which subsequently resulted in death of the MBCs (49).…”

Antibodies to PfSEA-1 block parasite egress from RBCs and protect against malaria infection

“…In all experiments, rPbSEA-1A generated significant protection. These results represent the first example of significantly reduced parasitemia and delayed mortality after vaccination with a blood-stage antigen in P. berghei ANKA (21). …”

Baculovirus-Vectored Multistage Plasmodium vivax Vaccine Induces Both Protective and Transmission-Blocking Immunities against Transgenic Rodent Malaria Parasites

“…Our strategy for evaluation of the BDES multistage vaccine used appropriately designed and phenotyped transgenic rodent malaria parasites for assessing murine immune responses to individual antigenic targets from a human malaria parasite. We and other groups have developed several transgenic rodent malaria parasites expressing human malaria antigens (e.g., PfCSP, PfMSP-1 19 , Pfs25, and Pvs25) to evaluate the immunogenicity and/or protective efficacy of vaccines (13,(15)(16)(17)(27)(28)(29)(30). Here, we describe the successful development of PvCSP [PvCSP(Sal)/Pb] transgenic P. berghei parasite expressing the full-length PvCSP-(Sal) in place of the natural P. berghei counterpart.…”

“…Such transgenic parasites provide a safe, cheap, and more practical alternative to using nonhuman primate models for preclinical challenge studies of malaria vaccine efficacy. Our previous studies have shown that BDES was an effective malaria vaccine platform for all three stages of the parasites, including the pre-erythrocytic stage (12,13), asexual blood stage (14,15), and sexual stage (16,17), when transgenic P. berghei parasites expressing human Plasmodium antigens were used for their evaluation. If optimized, BDES vaccines could be adopted for developing potent multistage malaria vaccines.…”